Title |
Long-Acting β2-Agonists Increase Fluticasone Propionate-Induced Mitogen-Activated Protein Kinase Phosphatase 1 (MKP-1) in Airway Smooth Muscle Cells
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Published in |
PLOS ONE, March 2013
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DOI | 10.1371/journal.pone.0059635 |
Pubmed ID | |
Authors |
Melanie Manetsch, Mostafizur Rahman, Brijeshkumar S. Patel, Emma E. Ramsay, Nowshin N. Rumzhum, Hatem Alkhouri, Qi Ge, Alaina J. Ammit |
Abstract |
Mitogen-activated protein kinase phosphatase 1 (MKP-1) represses MAPK-driven signalling and plays an important anti-inflammatory role in asthma and airway remodelling. Although MKP-1 is corticosteroid-responsive and increased by cAMP-mediated signalling, the upregulation of this critical anti-inflammatory protein by long-acting β2-agonists and clinically-used corticosteroids has been incompletely examined to date. To address this, we investigated MKP-1 gene expression and protein upregulation induced by two long-acting β2-agonists (salmeterol and formoterol), alone or in combination with the corticosteroid fluticasone propionate (abbreviated as fluticasone) in primary human airway smooth muscle (ASM) cells in vitro. β2-agonists increased MKP-1 protein in a rapid but transient manner, while fluticasone induced sustained upregulation. Together, long-acting β2-agonists increased fluticasone-induced MKP-1 and modulated ASM synthetic function (measured by interleukin 6 (IL-6) and interleukin 8 (IL-8) secretion). As IL-6 expression (like MKP-1) is cAMP/adenylate cyclase-mediated, the long-acting β2-agonist formoterol increased IL-6 mRNA expression and secretion. Nevertheless, when added in combination with fluticasone, β2-agonists significantly repressed IL-6 secretion induced by tumour necrosis factor α (TNFα). Conversely, as IL-8 is not cAMP-responsive, β2-agonists significantly inhibited TNFα-induced IL-8 in combination with fluticasone, where fluticasone alone was without repressive effect. In summary, long-acting β2-agonists increase fluticasone-induced MKP-1 in ASM cells and repress synthetic function of this immunomodulatory airway cell type. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 13 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 4 | 31% |
Researcher | 4 | 31% |
Student > Postgraduate | 2 | 15% |
Other | 2 | 15% |
Student > Bachelor | 1 | 8% |
Other | 0 | 0% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 3 | 23% |
Medicine and Dentistry | 3 | 23% |
Biochemistry, Genetics and Molecular Biology | 2 | 15% |
Immunology and Microbiology | 2 | 15% |
Nursing and Health Professions | 1 | 8% |
Other | 1 | 8% |
Unknown | 1 | 8% |